Eye on ID

Varicella: An annoying and potentially serious disease

Donald Kaye, MD, MACP
Donald Kaye

In previously healthy children, varicella (chickenpox), caused by varicella-zoster virus, or VZV, is almost always a mild disease. In fact, before the vaccine became available in the United States, “chickenpox parties” were a common occurrence in which children were brought to the house of someone with varicella so they could “share” the disease and develop an immunity after becoming infected. In the anti-vaccination communities, these “sharing parties” are still common. However, in the age of vaccination, this is not a good idea. The infection can be severe in infants and adults and is especially problematic during pregnancy and in immunocompromised individuals. The importance of varicella — in addition to the production of chickenpox and its complications — is twofold. First is the long-term persistence of the virus in latent form in sensory nerve ganglia, later developing into herpes zoster in many people, and second is the misdiagnosis of smallpox, which has implications of biowarfare, especially in war zones. As an example, a recent outbreak of chickenpox in Yemen (a country in the midst of a civil war and where there is no viral diagnostic capability) was initially reported by some news media as smallpox.

Incidence

The practice of vaccination against VZV, a herpesvirus, varies greatly from country to country. Therefore, the incidence of the disease varies greatly. Countries must have the resources to sustain at least an 80% rate of vaccination coverage to avoid shifting the disease to older age groups. In the absence of vaccination, the annual number of varicella cases in a country is close to its birth cohort. With widespread (universal) vaccination, like in the U.S., which has at least 90% coverage, the incidence of varicella is relatively low. Before the availability of vaccination in the U.S., varicella caused about 4 million cases yearly (the birth cohort), about 10,600 hospitalizations and 100 to 150 deaths. About 90% of the population had experienced varicella as children, leaving 10% of the adult population with no experience with the virus. Over the last 23 years in which vaccine has been available, the incidence of varicella has dropped by about 80% to over 90% in different studies using different means of measurement. In 2014, WHO estimated that approximately 4.2 million severe complications leading to hospitalization and 4,200 related deaths occur globally each year.

Pathogenesis and clinical syndrome

Varicella is extremely contagious. Although varicella is not as contagious as measles, nine of 10 household contacts of a person with varicella will become infected. Infection follows inhaling the virus via aerosolized nasopharyngeal secretions or by skin contact from an individual with varicella or with skin lesions of herpes zoster. Individuals with varicella may be infectious starting 2 days before rash onset and are infectious until all vesicles have formed scabs.

After entrance into the respiratory tract or conjunctivae, there is a long incubation period of 10 to 21 days (usually 14-16 days). There may be a 24- to 48-hour prodrome of fever and malaise. A rash then appears, usually first on the trunk and head and then progresses to involve the whole body. The rash consists of macules that rapidly become papules and then vesicles until they finally crust over, usually by 7 to 14 days. The rash appears in crops over the first few days, resulting in lesions in different stages of development in the same area. The trunk is more heavily involved with lesions than the extremities, and the palms and soles tend to be spared. The lesions can be extremely pruritic. Lesions can occur in the oropharynx, respiratory tract, vagina and on the conjunctiva and cornea. The rash of smallpox (when it occurred before eradication) did not come out in crops, so all lesions were in the same stage and the extremities tended to be heavily involved, often with rash on the palms and soles.

Varicella lesions on the face of a young child.
Varicella lesions on the face of a young child.
Source: CDC/Dr. John Noble, Jr.

Second attacks of varicella have been reported in immunocompetent individuals. Following exposure to varicella, about 20% of children who have received one dose of vaccine develop a mild attack of “breakthrough” varicella, which can infect others. This led to the recommendation in the U.S. in 2006 for the administration of two doses of vaccine.

At particular risk for complications are those aged older than 15 years, infants aged younger than 1 year, immunocompromised individuals and newborns of women who had rash onset 5 days before to 2 days after delivery. Those aged 45 years or older have a four to 50 times greater risk of hospitalization and 174-fold higher risk of dying than individuals aged 5 to 14 years. Before the availability of vaccine, about 11,000 people with varicella were hospitalized each year in the U.S. Hospitalization rates were approximately two to three per 1,000 cases among healthy children and eight per 1,000 cases among adults. Because the number of immunocompetent individuals infected was so much higher than those who were immunocompromised, most deaths were in the immunocompetent.

Complications

Complications of varicella include secondary staphylococcal or group A streptococcal infection of skin lesions, viral pneumonia and, less frequently, bacterial pneumonia. Children recovering from varicella who are given aspirin are at increased risk for Reye syndrome. Cerebellar ataxia in children may occur and is usually reversible. Rare central nervous system complications include aseptic meningitis, encephalitis, transverse myelitis and Guillain-Barré syndrome. Rarely, thrombocytopenia, hemorrhagic varicella, purpura fulminans, glomerulonephritis, myocarditis, arthritis, orchitis, uveitis, iritis and hepatitis have been reported. The most common complication in children is skin infection, and the most common complication in adults is pneumonia. Although radiographic pulmonary abnormalities are common in adults, clinical pneumonia is much less frequent. There is a high risk for disseminated disease in immunocompromised persons (up to 36% in one report), most often pneumonia and/or encephalitis.

It is estimated that 500,000 to 1 million episodes of herpes zoster occur annually in the U.S. The lifetime risk of herpes zoster is estimated to be at least 32%, and 50% of individuals living until age 85 years will develop herpes zoster. Herpes zoster occurs when cellular immunity declines as people age and the latent viruses in sensory nerve ganglia become activated. Herpes zoster caused by the varicella vaccine is rare. In fact, by preventing varicella, the vaccine probably decreases the possibility of later development of herpes zoster.

Diagnosis

Although diagnosis is easy in typical cases, especially in the presence of a known exposure, verification via PCR of vesicle fluid is often useful. The determination of whether the virus is a vaccine strain or a wild strain may be of importance. In some cases, as in Yemen recently, the question of smallpox may arise, and the demonstration of VZV may become necessary. In severe varicella, especially in immunocompromised persons, the syndrome may be atypical enough to raise questions about the diagnosis. In the absence of PCR, direct fluorescent antibody testing of the vesicle can be used; however, it is less sensitive than PCR.

Treatment

IV acyclovir has been used with success in some patients with complicated or very severe varicella infection. Oral acyclovir has a minor effect in shortening and ameliorating the course of the disease in typical cases; valacyclovir and famciclovir may be more effective. However, there is little to gain by treating the usual case of varicella in an immunocompetent child, and treatment is not recommended. Unvaccinated adolescents, adults, pregnant women and immunocompromised hosts should be treated.

Prevention

Varicella vaccine is a live-attenuated viral vaccine licensed in 1995 for patients aged 12 months and older. In 2005, a live-attenuated measles-mumps-rubella plus varicella vaccine was initially licensed for use in patients aged 12 months through 12 years. Because of a high incidence of breakthrough cases of varicella (about 20%), a second dose of varicella vaccine was recommended in 2006. The CDC recommends that the first dose be given at 12 to 15 months of age, and the second dose between the ages 4 and 6 years. The doses can be given at least 4 weeks apart in older children and adults. The incidence of breakthrough varicella is thought to be less than 10% with two doses of vaccine.

Health care workers should be screened for proof of immunity at the time of employment by virtue of having had varicella, by immunization with two injections of vaccine or by serological testing. In the absence of immunity, two injections of vaccine should be administered.

If someone is exposed to the virus and they have not had varicella before or if they have not received two doses of vaccine, they should be immunized within 3 to 5 days of exposure.

The vaccine should not be administered to individuals who are receiving immunosuppressive therapy or have primary or acquired immunodeficiencies because of the danger of disseminated disease. Varicella vaccine is also contraindicated for patients with neoplasms, neonates and pregnant women. If exposed to VZV, these patients should receive IV passive immunization (VariZIG). VariZIG will reduce the severity of varicella but not necessarily prevent it if given within 10 days of exposure.

Although it is too early to be certain, it is highly likely that by preventing varicella, the incidence of herpes zoster will significantly drop as the population ages. In fact, according to the CDC, “Children who get the varicella vaccine appear to have a lower risk of herpes zoster compared with people who were infected with wild-type VZV.”

Disclosure: Kaye reports no relevant financial disclosures.

Donald Kaye, MD, MACP
Donald Kaye

In previously healthy children, varicella (chickenpox), caused by varicella-zoster virus, or VZV, is almost always a mild disease. In fact, before the vaccine became available in the United States, “chickenpox parties” were a common occurrence in which children were brought to the house of someone with varicella so they could “share” the disease and develop an immunity after becoming infected. In the anti-vaccination communities, these “sharing parties” are still common. However, in the age of vaccination, this is not a good idea. The infection can be severe in infants and adults and is especially problematic during pregnancy and in immunocompromised individuals. The importance of varicella — in addition to the production of chickenpox and its complications — is twofold. First is the long-term persistence of the virus in latent form in sensory nerve ganglia, later developing into herpes zoster in many people, and second is the misdiagnosis of smallpox, which has implications of biowarfare, especially in war zones. As an example, a recent outbreak of chickenpox in Yemen (a country in the midst of a civil war and where there is no viral diagnostic capability) was initially reported by some news media as smallpox.

Incidence

The practice of vaccination against VZV, a herpesvirus, varies greatly from country to country. Therefore, the incidence of the disease varies greatly. Countries must have the resources to sustain at least an 80% rate of vaccination coverage to avoid shifting the disease to older age groups. In the absence of vaccination, the annual number of varicella cases in a country is close to its birth cohort. With widespread (universal) vaccination, like in the U.S., which has at least 90% coverage, the incidence of varicella is relatively low. Before the availability of vaccination in the U.S., varicella caused about 4 million cases yearly (the birth cohort), about 10,600 hospitalizations and 100 to 150 deaths. About 90% of the population had experienced varicella as children, leaving 10% of the adult population with no experience with the virus. Over the last 23 years in which vaccine has been available, the incidence of varicella has dropped by about 80% to over 90% in different studies using different means of measurement. In 2014, WHO estimated that approximately 4.2 million severe complications leading to hospitalization and 4,200 related deaths occur globally each year.

Pathogenesis and clinical syndrome

Varicella is extremely contagious. Although varicella is not as contagious as measles, nine of 10 household contacts of a person with varicella will become infected. Infection follows inhaling the virus via aerosolized nasopharyngeal secretions or by skin contact from an individual with varicella or with skin lesions of herpes zoster. Individuals with varicella may be infectious starting 2 days before rash onset and are infectious until all vesicles have formed scabs.

After entrance into the respiratory tract or conjunctivae, there is a long incubation period of 10 to 21 days (usually 14-16 days). There may be a 24- to 48-hour prodrome of fever and malaise. A rash then appears, usually first on the trunk and head and then progresses to involve the whole body. The rash consists of macules that rapidly become papules and then vesicles until they finally crust over, usually by 7 to 14 days. The rash appears in crops over the first few days, resulting in lesions in different stages of development in the same area. The trunk is more heavily involved with lesions than the extremities, and the palms and soles tend to be spared. The lesions can be extremely pruritic. Lesions can occur in the oropharynx, respiratory tract, vagina and on the conjunctiva and cornea. The rash of smallpox (when it occurred before eradication) did not come out in crops, so all lesions were in the same stage and the extremities tended to be heavily involved, often with rash on the palms and soles.

Varicella lesions on the face of a young child.
Varicella lesions on the face of a young child.
Source: CDC/Dr. John Noble, Jr.

Second attacks of varicella have been reported in immunocompetent individuals. Following exposure to varicella, about 20% of children who have received one dose of vaccine develop a mild attack of “breakthrough” varicella, which can infect others. This led to the recommendation in the U.S. in 2006 for the administration of two doses of vaccine.

At particular risk for complications are those aged older than 15 years, infants aged younger than 1 year, immunocompromised individuals and newborns of women who had rash onset 5 days before to 2 days after delivery. Those aged 45 years or older have a four to 50 times greater risk of hospitalization and 174-fold higher risk of dying than individuals aged 5 to 14 years. Before the availability of vaccine, about 11,000 people with varicella were hospitalized each year in the U.S. Hospitalization rates were approximately two to three per 1,000 cases among healthy children and eight per 1,000 cases among adults. Because the number of immunocompetent individuals infected was so much higher than those who were immunocompromised, most deaths were in the immunocompetent.

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Complications

Complications of varicella include secondary staphylococcal or group A streptococcal infection of skin lesions, viral pneumonia and, less frequently, bacterial pneumonia. Children recovering from varicella who are given aspirin are at increased risk for Reye syndrome. Cerebellar ataxia in children may occur and is usually reversible. Rare central nervous system complications include aseptic meningitis, encephalitis, transverse myelitis and Guillain-Barré syndrome. Rarely, thrombocytopenia, hemorrhagic varicella, purpura fulminans, glomerulonephritis, myocarditis, arthritis, orchitis, uveitis, iritis and hepatitis have been reported. The most common complication in children is skin infection, and the most common complication in adults is pneumonia. Although radiographic pulmonary abnormalities are common in adults, clinical pneumonia is much less frequent. There is a high risk for disseminated disease in immunocompromised persons (up to 36% in one report), most often pneumonia and/or encephalitis.

It is estimated that 500,000 to 1 million episodes of herpes zoster occur annually in the U.S. The lifetime risk of herpes zoster is estimated to be at least 32%, and 50% of individuals living until age 85 years will develop herpes zoster. Herpes zoster occurs when cellular immunity declines as people age and the latent viruses in sensory nerve ganglia become activated. Herpes zoster caused by the varicella vaccine is rare. In fact, by preventing varicella, the vaccine probably decreases the possibility of later development of herpes zoster.

Diagnosis

Although diagnosis is easy in typical cases, especially in the presence of a known exposure, verification via PCR of vesicle fluid is often useful. The determination of whether the virus is a vaccine strain or a wild strain may be of importance. In some cases, as in Yemen recently, the question of smallpox may arise, and the demonstration of VZV may become necessary. In severe varicella, especially in immunocompromised persons, the syndrome may be atypical enough to raise questions about the diagnosis. In the absence of PCR, direct fluorescent antibody testing of the vesicle can be used; however, it is less sensitive than PCR.

Treatment

IV acyclovir has been used with success in some patients with complicated or very severe varicella infection. Oral acyclovir has a minor effect in shortening and ameliorating the course of the disease in typical cases; valacyclovir and famciclovir may be more effective. However, there is little to gain by treating the usual case of varicella in an immunocompetent child, and treatment is not recommended. Unvaccinated adolescents, adults, pregnant women and immunocompromised hosts should be treated.

Prevention

Varicella vaccine is a live-attenuated viral vaccine licensed in 1995 for patients aged 12 months and older. In 2005, a live-attenuated measles-mumps-rubella plus varicella vaccine was initially licensed for use in patients aged 12 months through 12 years. Because of a high incidence of breakthrough cases of varicella (about 20%), a second dose of varicella vaccine was recommended in 2006. The CDC recommends that the first dose be given at 12 to 15 months of age, and the second dose between the ages 4 and 6 years. The doses can be given at least 4 weeks apart in older children and adults. The incidence of breakthrough varicella is thought to be less than 10% with two doses of vaccine.

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Health care workers should be screened for proof of immunity at the time of employment by virtue of having had varicella, by immunization with two injections of vaccine or by serological testing. In the absence of immunity, two injections of vaccine should be administered.

If someone is exposed to the virus and they have not had varicella before or if they have not received two doses of vaccine, they should be immunized within 3 to 5 days of exposure.

The vaccine should not be administered to individuals who are receiving immunosuppressive therapy or have primary or acquired immunodeficiencies because of the danger of disseminated disease. Varicella vaccine is also contraindicated for patients with neoplasms, neonates and pregnant women. If exposed to VZV, these patients should receive IV passive immunization (VariZIG). VariZIG will reduce the severity of varicella but not necessarily prevent it if given within 10 days of exposure.

Although it is too early to be certain, it is highly likely that by preventing varicella, the incidence of herpes zoster will significantly drop as the population ages. In fact, according to the CDC, “Children who get the varicella vaccine appear to have a lower risk of herpes zoster compared with people who were infected with wild-type VZV.”

Disclosure: Kaye reports no relevant financial disclosures.